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01-02-2007 | Original Article

Human interleukin 24 (MDA-7/IL-24) protein kills breast cancer cells via the IL-20 receptor and is antagonized by IL-10

Authors: Mingzhong Zheng, Dora Bocangel, Blair Doneske, Abner Mhashilkar, Rajagopal Ramesh, Kelly K. Hunt, Suhendan Ekmekcioglu, R. Bryan Sutton, Nancy Poindexter, Elizabeth A. Grimm, Sunil Chada

Published in: Cancer Immunology, Immunotherapy | Issue 2/2007

Abstract

The melanoma differentiation-associated gene-7 (mda-7/IL-24) is a unique member of the interleukin 10 (IL-10) family of cytokines, with ubiquitous tumor cell pro-apoptotic activity. Recent data have shown that IL-24 is secreted as a glycosylated protein and functions as a pro-Th1 cytokine and as a potent anti-angiogenic molecule. In this study, we analyzed the activity of Ad-mda7 and its protein product, secreted IL-24, against human breast cancer cells. We show that Ad-mda7 transduction of human breast cancer cells results in G₂/M phase cell cycle arrest and apoptotic cell death, which correlates with secretion of IL-24 protein. Neutralizing antibody against IL-24 significantly inhibited Ad-mda7 cytotoxicity. IL-24 and IL-10 both engage their cognate receptors on breast cancer cells resulting in phosphorylation and activation of STAT3, however, IL-10 receptor binding failed to induce cell killing, indicating that tumor cell killing by IL-24 is independent of STAT3 phosphorylation. Treatment with exogenous IL-24 induced apoptosis in breast cancer cells and this effect was abolished by addition of anti-IL-24 antibody or anti-IL-20R1, indicating that bystander cell killing is mediated via IL-24 binding to the IL-20R1/IL-20R2 heterodimeric receptor complex. Co-administration of the related cytokine IL-10 inhibited killing mediated by IL-24 and concomitantly inhibited IL-24 mediated up-regulation of the tumor suppressor proteins, p53 and p27^Kip1. In summary, we have defined a tumor-selective cytotoxic bystander role for secreted IL-24 protein and identified a novel receptor-mediated death pathway in breast cancer cells, wherein the related cytokines IL-24 and IL-10 exhibit antagonistic activity.

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Title: Human interleukin 24 (MDA-7/IL-24) protein kills breast cancer cells via the IL-20 receptor and is antagonized by IL-10
Authors: Mingzhong Zheng
Dora Bocangel
Blair Doneske
Abner Mhashilkar
Rajagopal Ramesh
Kelly K. Hunt
Suhendan Ekmekcioglu
R. Bryan Sutton
Nancy Poindexter
Elizabeth A. Grimm
Sunil Chada
Publication date: 01-02-2007
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 2/2007
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-006-0175-1

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